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Nucleic Acids Research 2004 32(17):5003-5010; doi:10.1093/nar/gkh831
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Published online 23 September 2004

Nucleic Acids Research, Vol. 32 No. 17 © Oxford University Press 2004; all rights reserved

The post-replication repair RAD18 and RAD6 genes are involved in the prevention of spontaneous mutations caused by 7,8-dihydro-8-oxoguanine in Saccharomyces cerevisiae

Marcelo de Padula, Guenaelle Slezak, Patricia Auffret van Der Kemp and Serge Boiteux*

CEA, Département de Radiobiologie et Radiopathologie, UMR217 CNRS ‘Radiobiologie Moléculaire et Cellulaire’, BP6, 92265-Fontenay aux Roses, France

* To whom correspondence should be addressed. Tel: +33 1 46 54 88 58; Fax: +33 1 46 54 88 59; Email: boiteux{at}dsvidf.cea.fr
Present address: Marcelo de Padula, LAMIAG-‘Universidade Federal do Rio de Janeiro’-UFRJ, CCS Faculdade de Farmácia, CEP: 21941-970 Rio de Janeiro, Brazil

Received July 19, 2004: Revised and Accepted August 30, 2004

7,8-Dihydro-8-oxoguanine (8-oxoG) is an abundant and mutagenic lesion produced in DNA exposed to free radicals and reactive oxygen species. In Saccharomyces cerevisiae, the OGG1 gene encodes the 8-oxoG DNA N-glycosylase/AP lyase (Ogg1), which is the functional homologue of the bacterial Fpg. Ogg1-deficient strains are spontaneous mutators that accumulate GC to TA transversions due to unrepaired 8-oxoG in DNA. In yeast, DNA mismatch repair (MMR) and translesion synthesis (TLS) by DNA polymerase {eta} also play a role in the prevention of the mutagenic effect of 8-oxoG. In the present study, we show the RAD18 and RAD6 genes that are required to initiate post-replication repair (PRR) are also involved in the prevention of mutations by 8-oxoG. Consistently, a synergistic increase in spontaneous CanR and Lys+ mutation rates is observed in the absence of Rad6 or Rad18 proteins in ogg1 mutant strains. Spectra of CanR mutations in ogg1 rad18 and ogg1 rad6 double mutants show a strong bias in the favor of GC to TA transversions, which are 137- and 189-fold higher than in the wild-type, respectively. The results also show that Pol{eta} (RAD30 gene product) plays a critical role on the prevention of mutations at 8-oxoG, whereas Pol{zeta} (REV3 gene product) does not. Our current model suggests that the Rad6–Rad18 complex targets Pol{eta} at DNA gaps that result from the MMR-mediated excision of adenine mispaired with 8-oxoG, allowing error-free dCMP incorporation opposite to this lesion.


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